Diabetes & Metabolism Journal

Letter

Two-Year Therapeutic Efficacy and Safety of Initial Triple Combination of Metformin, Sitagliptin, and Empagliflozin in Drug-Naïve Type 2 Diabetes Mellitus Patients (Diabetes Metab J 2024;48:253-64): Eun Young Lee; Diabetes Metab J. 2024;48(5):1005-1007. Published online September 12, 2024; DOI: https://doi.org/10.4093/dmj.2024.0417

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Brief Report

Complications
Diabetic Ketoacidosis as an Effect of Sodium-Glucose Cotransporter 2 Inhibitor: Real World Insights: Han-Sang Baek, Chaiho Jeong, Yeoree Yang, Joonyub Lee, Jeongmin Lee, Seung-Hwan Lee, Jae Hyoung Cho, Tae-Seo Sohn, Hyun-Shik Son, Kun-Ho Yoon, Eun Young Lee; Received January 22, 2024 Accepted May 13, 2024 Published online June 10, 2024; DOI: https://doi.org/10.4093/dmj.2024.0036 [Epub ahead of print]

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Abstract PDF PubReader ePub: One of the notable adverse effects of sodium-glucose cotransporter 2 (SGLT2) inhibitor is diabetic ketoacidosis (DKA) often characterized by euglycemia. In this retrospective review of patients with DKA from 2015 to 2023, 21 cases of SGLT2 inhibitorassociated DKA were identified. Twelve (57.1%) exhibited euglycemic DKA (euDKA) while nine (42.9%) had hyperglycemic DKA (hyDKA). More than 90% of these cases were patients with type 2 diabetes mellitus. Despite similar age, sex, body mass index, and diabetes duration, individuals with hyDKA showed poorer glycemic control and lower C-peptide levels compared with euDKA. Renal impairment and acidosis were worse in the hyDKA group, requiring hemodialysis in two patients. Approximately one-half of hyDKA patients had concurrent hyperosmolar hyperglycemic state. Common symptoms included nausea, vomiting, general weakness, and dyspnea. Seizure was the initial manifestation of DKA in two cases. Infection and volume depletion were major contributors, while carbohydrate restriction and inadequate insulin treatment also contributed to SGLT2 inhibitor-associated DKA. Despite their beneficial effects, clinicians should be vigilant for SGLT2 inhibitor risk associated with DKA.

Review

Basic Research
Rediscovering Primary Cilia in Pancreatic Islets: Eun Young Lee, Jing W. Hughes; Diabetes Metab J. 2023;47(4):454-469. Published online April 28, 2023; DOI: https://doi.org/10.4093/dmj.2022.0442

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Primary cilia are microtubule-based sensory and signaling organelles on the surfaces of most eukaryotic cells. Despite their early description by microscopy studies, islet cilia had not been examined in the functional context until recent decades. In pancreatic islets as in other tissues, primary cilia facilitate crucial developmental and signaling pathways in response to extracellular stimuli. Many human developmental and genetic disorders are associated with ciliary dysfunction, some manifesting as obesity and diabetes. Understanding the basis for metabolic diseases in human ciliopathies has been aided by close examination of cilia action in pancreatic islets at cellular and molecular levels. In this article, we review the evidence for ciliary expression on islet cells, known roles of cilia in pancreas development and islet hormone secretion, and summarize metabolic manifestations of human ciliopathy syndromes. We discuss emerging data on primary cilia regulation of islet cell signaling and the structural basis of cilia-mediated cell crosstalk, and offer our interpretation on the role of cilia in glucose homeostasis and human diseases.

Citations

Citations to this article as recorded by

Genome-wide association study and trans-ethnic meta-analysis identify novel susceptibility loci for type 2 diabetes mellitus
Asma A Elashi, Salman M Toor, Umm-Kulthum Ismail Umlai, Yasser A Al-Sarraj, Shahrad Taheri, Karsten Suhre, Abdul Badi Abou-Samra, Omar M E Albagha
BMC Medical Genomics.2024;[Epub] CrossRef
Reduced Nephrin Tyrosine Phosphorylation Enhances Insulin Secretion and Increases Glucose Tolerance With Age
Casey R Williamson, Nina Jones
Endocrinology.2024;[Epub] CrossRef
Beta-Hydroxybutyrate Promotes Basal Insulin Secretion While Decreasing Glucagon Secretion in Mouse and Human Islets
Risha Banerjee, Ying Zhu, George P Brownrigg, Renata Moravcova, Jason C Rogalski, Leonard J Foster, James D Johnson, Jelena Kolic
Endocrinology.2024;[Epub] CrossRef
Beta cell primary cilia mediate somatostatin responsiveness via SSTR3
Samantha E. Adamson, Zipeng A. Li, Jing W. Hughes
Islets.2023;[Epub] CrossRef

Original Articles

Clinical Care/Education
Physician-Directed Diabetes Education without a Medication Change and Associated Patient Outcomes: Hun-Sung Kim, Hyunah Kim, Hae-Kyung Yang, Eun Young Lee, Yoo Jin Jeong, Tong Min Kim, So Jung Yang, Seo Yeon Baik, Seung-Hwan Lee, Jae Hyoung Cho, In Young Choi, Hyeon Woo Yim, Bong-Yun Cha; Diabetes Metab J. 2017;41(3):187-194. Published online May 12, 2017; DOI: https://doi.org/10.4093/dmj.2017.41.3.187

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Background

When patients with diabetes mellitus (DM) are first referred to a hospital from primary health care clinics, physicians have to decide whether to administer an oral hypoglycemic agent (OHA) immediately or postpone a medication change in favor of diabetes education regarding diet or exercise. The aim of this study was to determine the effect of diabetes education alone (without alterations in diabetes medication) on blood glucose levels.

Methods

The study was conducted between January 2009 and December 2013 and included patients with DM. The glycosylated hemoglobin (HbA1c) levels were evaluated at the first visit and after 3 months. During the first medical examination, a designated doctor also conducted a diabetes education session that mainly covered dietary management.

Results

Patients were divided into those who received no diabetic medications (n=66) and those who received an OHA (n=124). Education resulted in a marked decrease in HbA1c levels in the OHA group among patients who had DM for <1 year (from 7.0%±1.3% to 6.6%±0.9%, P=0.0092) and for 1 to 5 years (from 7.5%±1.8% to 6.9%±1.1%, P=0.0091). Those with DM >10 years showed a slightly lower HbA1c target achievement rate of <6.5% (odds ratio, 0.089; P=0.0024).

Conclusion

For patients who had DM for more than 5 years, higher doses or changes in medication were more effective than intensive active education. Therefore, individualized and customized education are needed for these patients. For patients with a shorter duration of DM, it may be more effective to provide initial intensive education for diabetes before prescribing medicines, such as OHAs.

Citations

Citations to this article as recorded by

Management Status of Patients with Type 2 Diabetes Mellitus at General Hospitals in Korea: A 5-Year Follow-Up Study
Jin Hee Jung, Jung Hwa Lee, Hyang Mi Jang, Young Na, Hee Sun Choi, Yeon Hee Lee, Yang Gyo Kang, Na Rae Kim, Jeong Rim Lee, Bok Rye Song, Kang Hee Sim
The Journal of Korean Diabetes.2022; 23(1): 64. CrossRef
Effect of Voluntary Participation on Mobile Health Care in Diabetes Management: Randomized Controlled Open-Label Trial
Da Young Lee, Seung-Hyun Yoo, Kyong Pil Min, Cheol-Young Park
JMIR mHealth and uHealth.2020; 8(9): e19153. CrossRef
Developing a multi-center clinical data mart of ACEI and ARB for real-world evidence (RWE)
Hun-Sung Kim, Sue Hyun Lee, Tong Min Kim, Ju Han Kim
Clinical Hypertension.2018;[Epub] CrossRef

Effects of Spironolactone and Losartan on Diabetic Nephropathy in a Type 2 Diabetic Rat Model: Mi Young Lee, Myoung Sook Shim, Bo Hwan Kim, Soon Won Hong, Ran Choi, Eun Young Lee, Soo Min Nam, Gun Woo Kim, Jang Yel Shin, Young Goo Shin, Choon Hee Chung; Diabetes Metab J. 2011;35(2):130-137. Published online April 30, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.2.130

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Background

While there is an evidence that the anti-inflammatory properties of spironolactone can attenuate proteinuria in type 2 diabetes, its effects on vascular endothelial growth factor (VEGF) expression in diabetic nephropathy have not been clearly defined. In this study, we examined the effects of spironolactone, losartan, and a combination of these two drugs on albuminuria, renal VEGF expression, and inflammatory and oxidative stress markers in a type 2 diabetic rat model.

Methods

Thirty-three Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats were divided into four groups and treated with different medication regimens from weeks 25 to 50; OLETF diabetic controls (n=5), spironolactone-treated (n=10), losartan-treated (n=9), and combination of spironolactone- and losartan-treated (n=9).

Results

At week 50, the albumin-to-creatinine ratio was significantly decreased in the losartan and combination groups compared to the control OLETF group. No decrease was detected in the spironolactone group. There was a significant reduction in renal VEGF, transforming growth factor (TGF)-β, and type IV collagen mRNA levels in the spironolactone- and combination regimen-treated groups. Twenty-four hour urine monocyte chemotactic protein-1 levels were comparable in all four groups but did show a decreasing trend in the losartan and combination regimen groups. Twenty-four hour urine malondialdehyde levels were significantly decreased in the spironolactone- and combination regimen-treated groups.

Conclusion

These results suggest that losartan alone and a combined regimen of spironolactone and losartan could ameliorate albuninuria by reducing renal VEGF expression. Also, simultaneous treatment with spironolactone and losartan may have protective effects against diabetic nephropathy by decreasing TGF-β and type IV collagen expression and by reducing oxidative stress in a type 2 diabetic rat model.

Citations

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Tetrahydrocurcumin Add‐On therapy to losartan in a rat model of diabetic nephropathy decreases blood pressure and markers of kidney injury
Mahyar Khazaeli, Ane C. F. Nunes, Yitong Zhao, Mahziar Khazaali, John Prudente, Nosratola D. Vaziri, Bhupinder Singh, Wei Ling Lau
Pharmacology Research & Perspectives.2023;[Epub] CrossRef
Type 2 Diabetes Mellitus: Pathogenic Features and Experimental Models in Rodents
Inessa G. Gvazava, M. V. Karimova, A. V. Vasiliev, E. A. Vorotelyak
Acta Naturae.2022; 14(3): 57. CrossRef
Role of mineralocorticoid receptor antagonists in kidney diseases
Vishal Patel, Amit Joharapurkar, Mukul Jain
Drug Development Research.2021; 82(3): 341. CrossRef
Multi-strain probiotic supplement attenuates streptozotocin-induced type-2 diabetes by reducing inflammation and β-cell death in rats
Pei-Shan Hsieh, Hsieh-Hsun Ho, Shu Ping Tsao, Shih-Hung Hsieh, Wen-Yang Lin, Jui-Fen Chen, Yi-Wei Kuo, Shin-Yu Tsai, Hui-Yu Huang, Michael W. Greene
PLOS ONE.2021; 16(6): e0251646. CrossRef
Ocular surface complications in diabetes: The interrelationship between insulin and enkephalin
Indira Purushothaman, Ian S. Zagon, Joseph W. Sassani, Patricia J. McLaughlin
Biochemical Pharmacology.2021; 192: 114712. CrossRef
Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease
Daiji Kawanami, Yuichi Takashi, Yoshimi Muta, Naoki Oda, Dai Nagata, Hiroyuki Takahashi, Makito Tanabe
Frontiers in Pharmacology.2021;[Epub] CrossRef
Effects of single and dual RAAS blockade therapy on progressive kidney disease transition to CKD in rats
Devesh Aggarwal, Gaaminepreet Singh
Naunyn-Schmiedeberg's Archives of Pharmacology.2020; 393(4): 615. CrossRef
Bioactive Agent Discovery from the Natural Compounds for the Treatment of Type 2 Diabetes Rat Model
Shih-Chun Yang, Ching-Yun Hsu, Wei-Ling Chou, Jia-You Fang, Shih-Yi Chuang
Molecules.2020; 25(23): 5713. CrossRef
Losartan improves renal function and pathology in obese ZSF-1 rats
Zhi Su, Deborah Widomski, Arthur Nikkel, Laura Leys, Marian Namovic, Diana Donnelly-Roberts, Murali Gopalakrishnan, Steve McGaraughty
Journal of Basic and Clinical Physiology and Pharmacology.2018; 29(3): 281. CrossRef
Analyzing polymeric nanofibrous scaffold performances in diabetic animal models for translational chronic wound healing research
Nowsheen Goonoo, Archana Bhaw-Luximon
Nanotechnology Reviews.2017; 6(6): 583. CrossRef
Stimulatory effect of insulin on renal proximal tubule sodium transport is preserved in type 2 diabetes with nephropathy
Motonobu Nakamura, Nobuhiko Satoh, Masashi Suzuki, Haruki Kume, Yukio Homma, George Seki, Shoko Horita
Biochemical and Biophysical Research Communications.2015; 461(1): 154. CrossRef
Combination therapy with spironolactone and candesartan protects against streptozotocin-induced diabetic nephropathy in rats
Amal Hofni, Mohamed A. El-Moselhy, Ashraf Taye, Mohamed M. Khalifa
European Journal of Pharmacology.2014; 744: 173. CrossRef
Renal Protective Role of Xiexin Decoction with Multiple Active Ingredients Involves Inhibition of Inflammation through Downregulation of the Nuclear Factor-κB Pathway in Diabetic Rats
Jia-sheng Wu, Rong Shi, Jie Zhong, Xiong Lu, Bing-liang Ma, Tian-ming Wang, Bin Zan, Yue-ming Ma, Neng-neng Cheng, Fu-rong Qiu
Evidence-Based Complementary and Alternative Medicine.2013; 2013: 1. CrossRef
The use of animal models in diabetes research
Aileen JF King
British Journal of Pharmacology.2012; 166(3): 877. CrossRef
Effect of Eplerenone, a Selective Aldosterone Blocker, on the Development of Diabetic Nephropathy in Type 2 Diabetic Rats
Jae Hee Ahn, Ho Cheol Hong, Myong Jin Cho, Yoon Jung Kim, Hae Yoon Choi, Chai Ryoung Eun, Sae Jeong Yang, Hye Jin Yoo, Hee Young Kim, Ji A Seo, Sin Gon Kim, Kyung Mook Choi, Sei Hyun Baik, Dong Seop Choi, Nan Hee Kim
Diabetes & Metabolism Journal.2012; 36(2): 128. CrossRef

Review

The Role of Glomerular Podocytes in Diabetic Nephropathy.: Eun Young Lee, Choon Hee Chung; Korean Diabetes J. 2007;31(6):451-454. Published online November 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.6.451

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Abstract PDF

Diabetic nephropathy is the most common cause of end-stage renal disease and accounts for significant morbidity and mortality among individuals with diabetes mellitus. Therefore, the clarification of the pathogenesis of diabetic nephropathy is an urgent issue. Podocytes cover the outer layer of the glomerulus and maintain its integrity so that fluid and toxins exit in urine, but cells and important proteins are kept in the blood stream. Diabetes mellitus alters this structure, it becomes scarred and then the ability of the kidney to clear toxins is lost. Recent evidence shows that early in diabetes the podocyte number is reduced, areas of the glomerular basement membrane are denuded, and podocyte number predicts long-term urinary albumin excretion in the patients with diabetes and microalbuminuria. These results suggest that podocytes play a critical role in the early stage of diabetic nephropathy. It is the purpose of this article to review the pathogenetic role of podocytes in diabetic nephropathy.

Citations

Citations to this article as recorded by

Inhibition of dipeptidyl peptidase-4 (DPP4), antioxidant, antiglycation and anti-inflammatory effect of Ferulic acid against streptozotocin toxicity mediate nephropathy in diabetic rats
Maryam A. AL-Ghamdi, Said S. Moselhy
Environmental Science and Pollution Research.2022; 30(12): 33942. CrossRef
Study of Antiglycation, Hypoglycemic, and Nephroprotective Activities of the Green Dwarf Variety Coconut Water (Cocos nucifera L.) in Alloxan-Induced Diabetic Rats
Isabella F.D. Pinto, Railmara P. Silva, Adriano de B. Chaves Filho, Lucas S. Dantas, Vanderson S. Bispo, Isaac A. Matos, Felipe A.M. Otsuka, Aline C. Santos, Humberto Reis Matos
Journal of Medicinal Food.2015; 18(7): 802. CrossRef
Effects of ferulic acid on diabetic nephropathy in a rat model of type 2 diabetes
Ran Choi, Bo Hwan Kim, Jarinyaporn Naowaboot, Mi Young Lee, Mi Ri Hyun, Eun Ju Cho, Eun Soo Lee, Eun Young Lee, Young Chul Yang, Choon Hee Chung
Experimental and Molecular Medicine.2011; 43(12): 676. CrossRef

Original Articles

Effect of Peroxisome Proliferator Activated Receptor-gamma Agonist, Angiotensin II Receptor Blocker and alpha-lipoic Acid on Renal VEGF Expression in Diabetic Nephropathy.: Jang Hyun Koh, Yeon Lee, Mi Jin Kim, Young Goo Shin, Eun Young Lee, Choon Hee Chung; Korean Diabetes J. 2004;28(5):367-376. Published online October 1, 2004

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Abstract PDF: BACKGROUND
Diabetic nephropathy is one of the most serious complications in diabetes mellitus, and it is the leading cause of end stage renal disease. It has been reported that angiotensin converting enzyme inhibitor (ACEi) reduces the vascular endothelial growth factor (VEGF) expression, and so it plays an important role in reducing the renal damage. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonist is known to reduce insulin resistance in type 2 diabetic patients. In the previous study, PPAR-gamma agonist was shown to lower VEGF expression in the retina, but it increased the plasma VEGF level. Alpha-lipoic acid (alpha-LA), which is an antioxidant, lowers the increased level of VEGF in retina as well. The precise role of PPAR-gamma agonist and alpha-LA on renal VEGF expression in diabetic nephropathy is still uncertain. We studied the effect of PPAR-gamma agonist, angiotensin II receptor blocker (ATIIRB) and alpha-LA on the renal VEGF expression in diabetic rats. METHODS: We used 60 Sprague-Dawley male rats, those were 8 weeks old and weighted about 300 g each as the study subjects. Among them, 48 rats were chosen and injected with streptozotocin (70 mg/kg) into peritoneal cavity to induce diabetes mellitus. The rast were than divided into 5 groups. Group I was a normal control group (n=12), group II was diabetic control group (n=12), group III was diabetic group that was given with PPAR-gamma agonist (n=12), group IV was the diabetic group that was given ATIIRB (n=12), and group V was the diabetic rats that were given alpha-LA (n=12). We measured their body weight, blood glucose levels, 24 hour urine protein and albumin levels at the baseline, the 8th and the 16th weeks of the experiment. On the 16th weeks of our experiment we extracted the kidneys to measure the glomerular volume, the optical density of the VEGF staining and VEGF mRNA expression. RESULTS: At the beginning of the study, the 5 groups all showed similar 24 hour urine albumin levels. At the 8th week, group II showed an increased urine albumin level of 143.4 +/- 117.2 mg/day; this was greater than that of group IV (60.7+/-30.6 mg/day) (p<0.05). The glomerular volume and optical densities of VEGF expression were significantly reduced in group III, IV and V compared to group II. For group IV and V, the renal VEGF mRNA expression was significantly lower than that of group II, but group III showed no significant difference. from group II. CONCLUSION: Angiotensin II receptor blocker delayed the progression of diabetic nephropathy. PPAR-gamma agonist and alpha-lipoic acid did not have any protective effect against the progression of diabetic nephropathy in spite of the decreased VEGF expression noted in this study.

Mechanism of Podocyte Injury in Diabetic Nephropathy.: Eun Young Lee, Jae sook Song, Choon Hee Chung, Sae Yong Hong; Korean Diabetes J. 2003;27(4):343-351. Published online August 1, 2003

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Abstract PDF: BACKGROUND
Since podocytes are involved in the maintenance of filtration barrier and normal structure in the kidney, podocyte injury can cause the disturbance of glomerular permselectivity and resultant proteinuria, and recent evidence shows that podocyte injury is associated with oxidative stress. However, the pathogenetic mechanism of podocyte injury in the development of diabetic nephropathy is not known. Thus, the present study examined the effect of high glucose level on cytoskeleton, slit diaphragm, podocyte-glomerular basement membrane interaction, and oxidative stress in cultured podocytes. METHODS: Differentiated cultured podocytes were used in this study. Quiescent cells were incubated with culture media containing 30 mM glucose for 48 hours. The amounts of integrin alpha3, vinculin, zona occludens (ZO)-1 and fibronectin protein expressed by podocytes were measured by Western blot analysis. Dichlorofluorescein diacetate-sensitive intracellular reactive oxygen species (ROS) were observed by confocal microscope and quantified by quantification software. Thiobarbituric acid reactive substances were also measured. Podocytes incubated with culture media containing 5.6 mM glucose were used as control. RESULTS: Integrin alpha3 expression was significantly decreased in podocytes cultured under high glucose level compared to control. However, vinculin and ZO-1 expressions were significantly increased in podocytes cultured under high glucose level compared to control. Fibronectin protein secreted by podocytes was also increased in podocytes cultured under high glucose level compared to control. ROS and thiobarbituric acid reactive substances in podocytes were also increased in high glucose medium compared to control. CONCLUSION: High glucose-induced oxidative stress and the changes of integrin a3, ZO-1 and vinculin lead to the alterations of cytoskeleton, intercellular or cell-matrix interactions. This podocyte injury may play a major role in the disturbance of the urinary filtration barrier and the development of proteinuria. These results confirmed the important role of podocyte injury in the development of diabetic nephropathy.

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